The present invention relates to a non-human primate animal model infection system for the study of human papillomavirus (HPV) induced anongenital (including cervix, anus, penis), and potentially head-and-neck cancers, in particular the Rhesus papillomavirus (RhPV), cloned RhPV1 viral DNA and Rhesus cell culture models of infection.
Papillomaviruses (PVs) are a large family of nonenveloped, icosahedral DNA viruses with a particle diameter of 50-55 nm. PVs display remarkable species specificity and strong cellular tropism, and produce benign and malignant tumors in their natural hosts (8, 10, 14). Humans are the only known hosts for human papillomaviruses (HPVs); attempts to transfer HPVs to other species have failed (15). Complete genomes have been cloned for over 85 types of HPVs; 130 additional types have been partially characterized by PCR techniques (4). Only certain types of HPVs are associated with human cancers. For example, HPV1 and HPV2, types generally found in common and plantar warts, are not associated with carcinomas. HPV6 and HPV11, associated with laryngeal papillomatosis and anogenital lesions, rarely lead to carcinomas. The latter are known as low-risk viruses (2, 5). HPVs commonly associated with malignant conversion include those involved in epidermodysplasia verruciformis (e.g., HPV5 and HPV8) and a subset of the types that infect the anogenital region. Examples of the high-risk anogenital viruses include HPV types 16, 18, 31, 33 and 51 (1, 2, 5, 6). High-risk HPV infections are involved in greater than 99% of all anogenital malignancies (Walboomers, J. M. M., M. V. Jacobs, M. M. Manos, F. X. Bosch, J. A. Kummer, K. V. Shah, P. J. F. Snijders, J. Peto, C. J. L. M. Meijer, and N. Muñoz. (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 189: 12-19), and cervical cancer is the second leading cause of cancer-related deaths in women worldwide (13). High-risk HPVs are also associated with head-and-neck cancers (Gillison, M. L., W. M. Koch, R. B. Capone, M. Spafford, W. H. Westra, L. Wu, M. L. Zahurak, R. W. Daniel, M. Viglione, D. E. Symer, K. V. Shah, and D. Sidransky. (2000) Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers. JNCI Cancer Spectrum 92: 709-720) The capacity of HPVs to cause malignancies can be partially attributed to their ability to establish persistent infections (7). Thus, high risk HPVs pose a serious public health problem.
Viral particles from high-risk HPV types are produced only in small amounts in vivo (Pfister, H. (1984) Biology and biochemistry of papillomaviruses. Rev. Physiol. Biochem. Pharmacol. 99: 111-181) and the ability to obtain quantities of virions necessary for infectivity studies has been severely limited for high-risk HPVs, inhibiting many studies of HPV biology. There have been no reports of viral particle isolation from the typically small anogenital lesions that can progress to malignancies. This has inhibited many studies of PV biology. The organotypic (raft) tissue culture system is the only in vitro system proven to consistently mimic epithelial differentiation to the extent that infectious high-risk PVs can be purified.
There is currently no animal model system to study genital PV infections in vivo. However, a PV genome was recently recovered from a rhesus monkey with a metastatic tumor arising from a penile carcinoma (12). This virus, named RhPV1 for rhesus PV type 1, was found to be sexually transmitted among rhesus monkeys (12). Only four papers have been published on this RhPV1 genome. The first paper describes the discovery and initial cloning of the genome from a male with a lymph node metastasis of a squamous cell carcinoma of the penis (9). In the second paper, the authors determine the biological significance of the genome by showing RhPV1 infections occurred in a population of female monkeys who were sexually active with the index male (12). The third paper describes the characterization of the genome and its integration locus in the host DNA (11). The fourth paper looks at the evolutionary conservation of this viral genome and determines that RhPV1 is closely related to HPV types 16, 31, and 33, causes of human anogenital and head-and-neck cancers (3).
There is a longfelt need in the art for an animal model, especially a non-human primate animal model, infection system, in which to study of PV infection and PV-induced (i.e. all) anogenital cancers. Such a system would permit the study of the natural history of PV infection, including transmission, immunology, acute and chronic pathology (neoplasia), and progression to malignancy of PV infections, as well as testing of potential prophylactic and therapeutic agents. This model will also likely have great impact on our understanding of the role of HPVs in head-and-neck cancers. The present invention using RhPV fulfills this need.